title: New glucocerebrosidase inhibitors by exploration of chemical diversity of N-substituted aminocyclitols using click chemistry and in situ screening.
abstract: A library of aminocyclitols derived from CuAAC reaction between N-propargylaminocyclitol 4 and a series of azides [1-25] is described and tested against GCase. Azides have been chosen from a large collection of potential candidates that has been filtered according to physical and reactivity constraints. A synthetic methodology has been optimized in order to avoid the use of protecting groups on the aminocyclitol scaffold. Because the reaction can be carried out in an aqueous system, the resulting library members can be screened in situ with minimal manipulation. From the preliminary GCase inhibition data, the most potent library members have been individually resynthesized for further biological screening and complete characterization. Some of the library members have shown biochemical data (IC(50), K(i), and stabilization ratio) similar or superior to those reported for NNDNJ. Docking studies have been used to postulate ligand-enzyme interactions to account for the experimental results.
authors.affiliation: Spanish National Research Council (Consejo Superior de Investigaciones Científicas), Research Unit on Bioactive Molecules (RUBAM), Departament de Química Biomèdica, Institut de Química Avançada de Catalunya, Jordi Girona 18-26, 08034 Barcelona, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: Díaz
authors.forename: Josefina
authors.initials: J
authors.lastname: Casas
authors.forename: Jordi
authors.initials: J
authors.lastname: Bujons
authors.forename: Amadeu
authors.initials: A
authors.lastname: Llebaria
authors.forename: Antonio
authors.initials: A
authors.lastname: Delgado
mesh_terms: D057930:Click Chemistry; D054812:Cyclitols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011487:Protein Conformation; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D054812:Cyclitols; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D005962:Glucosylceramidase